scholarly journals SMK-1/PPH-4.1–mediated silencing of the CHK-1 response to DNA damage in early C. elegans embryos

2007 ◽  
Vol 179 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Seung-Hwan Kim ◽  
Antonia H. Holway ◽  
Suzanne Wolff ◽  
Andrew Dillin ◽  
W. Matthew Michael
Keyword(s):  
Dna Damage ◽  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Germ Line ◽  
Embryonic Cell ◽  
Regulatory Subunit ◽  
Ataxia Telangiectasia Mutated ◽  
C Elegans ◽  
Early Embryos ◽  
Embryonic Cell Cycle

During early embryogenesis in Caenorhabditis elegans, the ATL-1–CHK-1 (ataxia telangiectasia mutated and Rad3 related–Chk1) checkpoint controls the timing of cell division in the future germ line, or P lineage, of the animal. Activation of the CHK-1 pathway by its canonical stimulus DNA damage is actively suppressed in early embryos so that P lineage cell divisions may occur on schedule. We recently found that the rad-2 mutation alleviates this checkpoint silent DNA damage response and, by doing so, causes damage-dependent delays in early embryonic cell cycle progression and subsequent lethality. In this study, we report that mutations in the smk-1 gene cause the rad-2 phenotype. SMK-1 is a regulatory subunit of the PPH-4.1 (protein phosphatase 4) protein phosphatase, and we show that SMK-1 recruits PPH-4.1 to replicating chromatin, where it silences the CHK-1 response to DNA damage. These results identify the SMK-1–PPH-4.1 complex as a critical regulator of the CHK-1 pathway in a developmentally relevant context.

scholarly journals A Novel ATM-Dependent Pathway Regulates Protein Phosphatase 1 in Response to DNA Damage

2008 ◽  
Vol 28 (8) ◽  
pp. 2559-2566 ◽  
Author(s):  
Xi Tang ◽  
Zhou-guang Hui ◽  
Xiao-li Cui ◽  
Renu Garg ◽  
Michael B. Kastan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Phosphatase ◽  
Cellular Response ◽  
Cellular Responses ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Aurora B ◽  
Major Protein ◽  
Ataxia Telangiectasia Mutated ◽  
Dependent Pathway

ABSTRACT Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses. In response to IR, ATM phosphorylates I-2 on serine 43, leading to the dissociation of the PP1-I-2 complex and the activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in the inhibition of the Aurora-B kinase, the down-regulation of histone H3 serine 10 phosphorylation, and the activation of the G2/M checkpoint. Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage.

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

2021 ◽  
Author(s):  
Bing Sun ◽  
McLean Sherrin ◽  
Richard Roy
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Germ Line ◽  
Critical Role ◽  
Significant Proportion ◽  
Loop Formation ◽  
C Elegans ◽  
Chromatin Activation ◽  
Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

scholarly journals PR48, a Novel Regulatory Subunit of Protein Phosphatase 2A, Interacts with Cdc6 and Modulates DNA Replication in Human Cells

2000 ◽  
Vol 20 (3) ◽  
pp. 1021-1029 ◽  
Author(s):  
Zhen Yan ◽  
Sergei A. Fedorov ◽  
Marc C. Mumby ◽  
R. Sanders Williams
Keyword(s):  
Dna Replication ◽  
Protein Phosphatase ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Protein Phosphatase 2A ◽  
Specific Interaction ◽  
Regulatory Subunit ◽  
Amino Terminal ◽  
Phosphatase 2A ◽  
Initiation Of Dna Replication

ABSTRACT Initiation of DNA replication in eukaryotes is dependent on the activity of protein phosphatase 2A (PP2A), but specific phosphoprotein substrates pertinent to this requirement have not been identified. A novel regulatory subunit of PP2A, termed PR48, was identified by a yeast two-hybrid screen of a human placental cDNA library, using human Cdc6, an essential component of prereplicative complexes, as bait. PR48 binds specifically to an amino-terminal segment of Cdc6 and forms functional holoenzyme complexes with A and C subunits of PP2A. PR48 localizes to the nucleus of mammalian cells, and its forced overexpression perturbs cell cycle progression, causing a G1 arrest. These results suggest that dephosphorylation of Cdc6 by PP2A, mediated by a specific interaction with PR48, is a regulatory event controlling initiation of DNA replication in mammalian cells.

scholarly journals The Nucleolus ofCaenorhabditis elegans

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Li-Wei Lee ◽  
Chi-Chang Lee ◽  
Chi-Ruei Huang ◽  
Szecheng J. Lo
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Size Control ◽  
Cell Types ◽  
C Elegans ◽  
Homologous Genes ◽  
Early Embryos ◽  
Human Disorders ◽  
Nucleolar Size

Nucleolar size and appearance correlate with ribosome biogenesis and cellular activity. The mechanisms underlying changes in nucleolar appearance and regulation of nucleolar size that occur during differentiation and cell cycle progression are not well understood.Caenorhabditis elegansprovides a good model for studying these processes because of its small size and transparent body, well-characterized cell types and lineages, and because its cells display various sizes of nucleoli. This paper details the advantages of usingC. elegansto investigate features of the nucleolus during the organism's development by following dynamic changes in fibrillarin (FIB-1) in the cells of early embryos and aged worms. This paper also illustrates the involvement of thencl-1gene and other possible candidate genes in nucleolar-size control. Lastly, we summarize the ribosomal proteins involved in life span and innate immunity, and those homologous genes that correspond to human disorders of ribosomopathy.

scholarly journals ATM and ATR Influence Meiotic Crossover Formation Through Antagonistic and Overlapping Functions inC. elegans

2019 ◽  
Author(s):  
Wei Li ◽  
Judith Yanowitz
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Molecular Networks ◽  
Ataxia Telangiectasia Mutated ◽  
Cycle Progression ◽  
Strand Breaks ◽  
Regulatory Processes ◽  
Damage Response ◽  
Repair Template

ABSTRACTDuring meiosis, formation of double-strand breaks (DSBs) and repair by homologous recombination between homologs creates crossovers (COs) that facilitate chromosome segregation. CO formation is tightly regulated to ensure the integrity of this process. The DNA damage response kinases, Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) have emerged as key regulators of CO formation in yeast, flies, and mice, influencing DSB formation, repair pathway choice, and cell cycle progression. The molecular networks that ATM and ATR influence during meiosis are still being resolved in other organisms. Here we show thatCaenorhabditis elegansATM and ATR homologs, ATM-1 and ATL-1 respectively, act at multiple steps in CO formation to ultimately ensure that COs are formed on all chromosomes. We show a role for ATM-1 in regulating the choice of repair template, biasing use of the homologous chromosome instead of the sister chromatid. Our data suggests a model in which ATM-1 and ATL-1 have antagonistic roles in very early repair processing, but are redundantly required for accumulation of the RAD-51 recombinase at DSB sites. We propose that these features of ATM-1 and ATL-1 ensure both CO formation on all chromosomes and accurate repair of additional DSBs.Article SummaryCrossovers formed during meiosis connect homologs and properly align them for cell division. The central importance of crossovers is underscored by the existence of extensive regulatory processes that ensures the proper execution of these events. This paper explores the evolutionary conserved roles of the central DNA damage response kinases, ATM and ATR, in crossover formation. The authors show that these kinases function together as rheostats to promote timely formation of crossovers on all chromosomes but to limit extensive DNA damage. This work provides a platform for identifying conserved meiotic targets of ATM and ATR that affect fertility across species.

scholarly journals Excess histone H3 is a Chk1 inhibitor that controls embryonic cell cycle progression

2020 ◽  
Author(s):  
Yuki Shindo ◽  
Amanda A. Amodeo
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Histone H3 ◽  
Embryonic Cell ◽  
Cycle Progression ◽  
Cell Cycles ◽  
Embryonic Cell Cycle

AbstractThe early embryos of many species undergo a switch from rapid, reductive cleavage divisions to slower, cell fate-specific division patterns at the Mid-Blastula Transition (MBT). The maternally loaded histone pool is used to measure the increasing ratio of nuclei to cytoplasm (N/C ratio) to control MBT onset, but the molecular mechanism of how histones regulate the cell cycle has remained elusive. Here, we show that excess histone H3 inhibits the DNA damage checkpoint kinase Chk1 to promote cell cycle progression in the Drosophila embryo. We find that excess H3-tail that cannot be incorporated into chromatin is sufficient to shorten the embryonic cell cycle and reduce the activity of Chk1 in vitro and in vivo. Removal of the Chk1 phosphosite in H3 abolishes its ability to regulate the cell cycle. Mathematical modeling quantitatively supports a mechanism where changes in H3 nuclear concentrations over the final cell cycles leading up to the MBT regulate Chk1-dependent cell cycle slowing. We provide a novel mechanism for Chk1 regulation by H3, which is crucial for proper cell cycle remodeling during early embryogenesis.

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